Objective
To explore parental experiences of whole exome sequencing (WES) for prenatal diagnosis and ascertain what influenced their decision‐making to undergo testing.
Method
Twelve women comprised ...a purposeful sample in a series of semistructured interviews. All had received a fetal anomaly diagnosis on ultrasound. A topic guide was used, and transcripts were thematically analyzed to elicit key themes.
Results
Five main themes (parental experiences of prenatal WES, need for information, consent/reasons for prenatal WES, sources of support for prenatal WES, and return of WES findings to families) emerged, some with multiple subthemes.
Conclusions
Parents desired as much information as possible and appreciated information being repeated and provided in various formats. Many struggled with clinical uncertainty relating to the cause and prognosis following a fetal anomaly diagnosis and found it difficult to balance the risks of invasive testing against their need for more definitive information. Parents trusted their clinicians and valued their support with decisions in pregnancy. Testing was sometimes pursued to reassure parents that their baby was “normal” rather than to confirm an underlying genetic problem. Parents were motivated to undergo WES for personal and altruistic reasons but disliked waiting times for results and were uncertain about what findings might be returned.
What is already known about this topic?
Prenatal WES for genetic diagnosis is possible, but little is known regarding parental experiences of prenatal sequencing.
What does this study add?
Parents require specific information to help them decide whether to undergo WES for prenatal diagnosis.
Appropriate counseling is essential for informed consent.
Parents require explanation about what WES might identify and how and when findings are returned.
OBJECTIVE
To (a) evaluate the proportion of women where a unifying genetic diagnosis was obtained following assessment of an observed pattern of fetal anomalies and (b) assess trends in genetic ...testing in a joint fetal‐medicine genetic clinic.
METHOD
Retrospective cohort study of all women attending the clinic. Outcomes included (a) indication for referral, (b) genetic test performed and (c) diagnoses obtained.
RESULTS
From 2008 to 2019, 256 patients were referred and reviewed, of which 23% (n = 59) were consanguineous. The main indication for referral was the observed pattern of fetal anomalies. Over 10 years, the number of patients reviewed increased from 11 to 35 per annum. A unifying genetic diagnosis was obtained in 43.2% (n = 79/183), the majority of which were diagnosed prenatally (50.6% n = 40/79). The main investigation(s) that was the ultimate diagnostic test was targeted gene panel sequencing 34.2% (n = 27/79), with this and exome sequencing becoming the dominant genetic test by 2019. Pregnancies reviewed due to an abnormal karyotype or microarray decreased as an indication for referral during the study period (21.6% n = 16/74 2008‐2012 vs 16.5% n = 30/182 in 2012‐2019).
CONCLUSION
A prenatal genetic clinic with a structured multi‐disciplinary team approach may be successful in obtaining a unifying prenatal genetic diagnosis.
Objective
Evaluate the diagnostic yield of prenatal submicroscopic chromosome anomalies using prenatal array comparative genomic hybridisation (aCGH).
Method
Prospective cohort study conducted ...between March 2013 and June 2017 including fetuses where an elevated nuchal translucency (NT) or structural anomaly was identified on ultrasound and common aneuploidy testing was negative. aCGH was performed using an 8‐plex oligonucleotide platform with a genome wide backbone resolution of greater than 200 kb and interpretation in line with American College of Medical Genetics guidance.
Results
One thousand one hundred twenty‐nine fetuses were included; 371 fetuses with an increased NT (32.9%) and 758 with a structural anomaly (67.1%). The rate of pathogenic copy number variants (CNVs) and variant of uncertain significance (VUS) was 5.9% (n = 22) and 0.5% (n = 2) in the elevated NT group and 7.3% (n = 55) and 0.8% (n = 6) in the mid‐trimester anomaly group. No pathogenic CNVs were identified in fetuses with an NT less than 4.0 mm. Multisystem and cardiac anomalies had the greatest yield of pathogenic CNV with a 22q11.2 microdeletion present in 40% (12/30).
Conclusion
Prenatal aCGH is a useful diagnostic tool in the investigation of fetuses with a significantly elevated NT or structural anomaly. With time and experience, rates of pathogenic CNVs have increased, and VUS have reduced, supporting the prenatal application of increasingly high resolution aCGH platforms.
What is already known about this topic?
Chromosome Microarray Analysis (CMA) provides an additional genetic diagnostic yield (sub‐microscopic deletions/rearrangements) of 3% to 5% over and above standard testing strategies in fetuses with structural anomalies.
What does this study add?
This study assesses the clinical utility of CMA in the current day and demonstrates that with time and experience the diagnostic yield for fetal structural anomalies has doubled with significantly lower rates of variants of uncertain significance (0.6%).
The objective was to gain insight into the experiences of women and their partners diagnosed with a fetal abnormality on prenatal ultrasound examination and receiving genetic testing including ...microarray. Twenty-five semi-structured interviews were performed with women +/- their partners after receiving the results of prenatal genetic testing. Framework analysis was performed to elicit themes and subthemes. Five main themes were recognized; diagnosis, genetic testing, family and support, reflections of the treatment received and emotions. Our results showed that women recall being told about QFPCR for trisomy 13, 18, and 21 but often no further testing. Women expected the conventional karyotype and microarray result would be normal following a normal QFPCR result. There were frequent misconceptions by couples regarding aspects of counseling/testing. Communication of variants of unknown (clinical) significance (VOUS) presents a particularly difficult challenge. Good clear communication by health care professionals is paramount. When counseling women and their partners for fetal chromosomal testing it should be reinforced that although the most common, trisomy 13, 18, and 21 only account for some of the chromosomal changes resulting in abnormal scan findings. Couples should have literature to take home summarizing scan anomalies and reinforcing information about genetic testing.
Nager syndrome is a rare, complex malformation syndrome, for which there is limited information on prenatal genetic testing. Clinical diagnosis of Nager syndrome, which can be caused by deletions ...encompassing SF3B4 gene, is possible prenatally. Prenatal chromosomal microarray can aid genotype‐phenotype correlation in pregnancies with structural abnormalities seen on ultrasound.
Nager syndrome is a rare, complex malformation syndrome, for which there is limited information on prenatal genetic testing. Clinical diagnosis of Nager syndrome, which can be caused by deletions encompassing SF3B4 gene, is possible prenatally. Prenatal chromosomal microarray can aid genotype‐phenotype correlation in pregnancies with structural abnormalities seen on ultrasound.
Key Clinical Message
The loss of ANKRD11 gene confirms the diagnosis of KBG syndrome but does not elucidate the pediatric phenotype providing a counseling challenge. With the expansion of prenatal ...diagnosis, and the potential to perform whole‐exome sequencing antenatally, we must describe the genetic abnormalities, antenatal ultrasound findings, and phenotype concurrently to facilitate counseling.
The loss of ANKRD11 gene confirms the diagnosis of KBG syndrome but does not elucidate the pediatric phenotype providing a counseling challenge. With the expansion of prenatal diagnosis, and the potential to perform whole‐exome sequencing antenatally, we must describe the genetic abnormalities, antenatal ultrasound findings, and phenotype concurrently to facilitate counseling.
Advances in prenatal genomics have enabled the assessment of not only the sub-microscopic structure of chromosomes using chromosomal microarray analysis, but also the detection of “pathogenic ...variants” to the resolution of a single base pair with the use of next generation sequencing. Research is emerging on the additional prenatal diagnostic yield that exome sequencing offers when structural fetal anomalies are detected on ultrasound examination, in particular the identification of monogenic abnormalities defining prognosis and recurrence of anomalies. Primarily assessed using fetal DNA obtained by invasive techniques (amniocytes or chorionic villi), this technology is progressing into a non-invasive approach using maternal plasma. There are several challenges, to be addressed before this technology can be introduced into routine clinical practice. These are primarily technical and interpretational but also relate to service provision; cost-effectiveness; turn-around time; patient acceptability and ethical dilemmas. With adequate pre- and post-test counselling many of these challenges may be overcome and such counselling has to be multi-disciplinary, involving clinical geneticists, genetic scientists, paediatricians, perinatal pathologists and fetal medicine subspecialists. There is therefore a need for obstetricians to have an understanding of the clinical utility, application, advantages and challenges of such technologies before introduction into routine clinical practice.
Key Clinical Message
The loss of
ANKRD
11 gene confirms the diagnosis of
KBG
syndrome but does not elucidate the pediatric phenotype providing a counseling challenge. With the expansion of prenatal ...diagnosis, and the potential to perform whole‐exome sequencing antenatally, we must describe the genetic abnormalities, antenatal ultrasound findings, and phenotype concurrently to facilitate counseling.
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